疾患について
Acute hepatic porphyria (AHP)
Overview
The porphyrias are a set of metabolic disorders, each representing a defect in one of the eight enzymes in the heme biosynthetic pathway that results in the accumulation of organic compounds called porphyrins. This leads to the clinical and biochemical profile typical for each porphyria. Hepatic porphyrias are those in which the enzyme deficiency occurs in the liver.
Hepatic porphyrias include:
- acute intermittent porphyria (AIP),
- variegate porphyria (VP),
- aminolevulinic acid dehydratase deficiency porphyria (ALAD),
- hereditary coproporphyria (HCP), and
- porphyria cutanea tarda (PCT).
The acute hepatic porphyrias clinically present with neurological attacks (seizures, psychosis, severe abdominal and back pain, and acute polyneuropathy) and, to a lesser extent, with cutaneous manifestations such as photosensitive blistering rash or hypertrichosis.
The worldwide prevalence of acute hepatic porphyrias ranges from one in 500 to one in 50,000 individuals ; with all racial and ethnic groups affected by. In most regions, AIP is the most common, and ALAD is the least common. The prevalence of AIP presenting with clinical manifestations is reported to be 5 to 10 per 100,000 individuals, while the prevalence of genetic mutations of AIP is approximately one in 1675 individuals. VP, which is rarer, has a reported prevalence of 4 to 13 cases per million individuals and a prevalence calculated to be approximately 3 symptomatic cases per million individuals. Of note, although AIP, VP, and HCP are AD disorders and thus, expected to affect men and women equally. However, AIP has demonstrated a female bias, with reports of attacks being five times more frequent in non-Hispanic females as compared with males.
The treatment goal for an acute attack of hepatic porphyria is to abate the attack as quickly as possible and to provide appropriate supportive care and symptomatic care until the acute attack resolves. Hospitalization is usually required. Therapy requires confirmation that the patient indeed has acute porphyria, based on the finding of elevated urinary porphobilinogen (PBG), either at present or previously. Still, it does not require a diagnosis of the exact type of acute porphyria. In a patient known to have acute porphyria based on prior testing, the presence of an acute attack is largely established clinically1.
Diagnosis
The first step of AP diagnosis is to- measure urine porphobilinogen (PBG), total porphyrins and creatinine using a spot (random, single void) urine sample.
- PBG can be measured in plasma or serum in patients with advanced renal disease, but plasma levels are less elevated than in urine in patients with normal renal function2.
Symptoms
Patients with AP may develop the following signs and symptoms, which can vary from one patient to another:- Severe abdominal pain is the most common and often the initial symptom of an attack. It is typically generalized rather than localized, and is often accompanied by nausea, vomiting, distension, constipation or diarrhea. Pain is typically severe, with few of the physical findings found in inflammatory conditions such as appendicitis.
- Peripheral neuropathy can be manifested as pain in multiple areas such as the back, buttocks, chest or limbs. Paresis may develop and progress, especially with an advanced attack. Early detection of paresis, which often begins proximally in the upper extremities, requires a careful neurological examination.
- Central and autonomic nervous system involvement may cause mental status changes, seizures, psychosis, insomnia and anxiety. Hypothalamic involvement can cause the syndrome of inappropriate antidiuretic hormone production (SIADH), leading to hyponatremia. Autonomic nervous system manifestations include tachycardia, hypertension and bladder dysfunction with urinary retention, incontinence, and dysuria)
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Causes
Porphyrias are due to an absence of enzymes of the porphyrin pathway, causing abnormally elevated concentrations of these heme precursors, which are toxic to tissues at high levels. Porphyrins are the major precursors of heme, an important component of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes1.What happens during an attack?
Acute attacks almost always start with severe unexplained pain, usually in the abdomen but sometimes in the back or thighs. It is also quite common to have nausea, vomiting and constipation. Acute porphyria can also affect the nervous system causing numbness and muscle weakness. This can even occur in the chest wall, which can in turn lead to breathing difficulties. These symptoms can become very severe and even life-threatening if not managed early, so it is vital that a doctor is seen as soon as an attack begins. Many acute attacks are triggered by avoidable causes, such as alcohol, medications and low-calorie diets. Variations in hormone levels are also a common factor, which is why females tend to experience attacks more than males. With proper drug therapy, acute porphyria progression can be halted or symptoms can be reduced.For more information on the safe drugs’ list, please check www.drugs-porphyria.org
Recordati Rare Diseases is supporting the International Porphyria Network (IPNET) in the development of information for patients and families.
Recordati Rare Diseases has also supported the development of information for patients and their families. Click on the picture below to download the patients’ brochure.
Patient organisations
Our list of patient organisations may be incomplete. Please help us keep this updated bycontacting us.- International– International Porphyria Community –www.rareconnect.org/en/community/porphyria
- Canada– Canadian Association for Porphyria –canadianassociationforporphyria.ca/
- Denmark– Danish Porphyria Support Group –www.porfyrier.dk
- France– Association française des malades attaints de porphyries – www.porphyries-patients.org
- Germany – EPP Deutschland –www.epp-deutschland.de
- Italy– Associazione Malati di Porfiria (AMAPO) –www.amapo.it
- Japan– Sakura Friends –www.sakuratomonokai.com
- Mexico– Porfiria Mexico –www.porfiriamexico.com
- Netherlands– Dutch EPP Association –www.epp.info
- Norway– Norwegian Porphyria Centre (NAPOS) –www.napos.no
- Poland– Stowarzyszenie Porfiria Polska –www.porfiria.com.pl
- South Africa– Porphyria South Africa –www.porphyria.uct.ac.za
- Spain– Associacion Espanola de porfiria –www.porfiria.org
- Sweden– Riksföreningen Mot Porfyrisjukdomar (RMP) –www.porfyri.se
- Switzerland – SGP –www.porphyria.ch
- United Kingdom– British Porphyria Association –www.porphyria.org.uk
- USA– American Porphyria Foundation –www.porphyriafoundation.org
References
- Kothadia JP, LaFreniere K, Shah JM. Acute Hepatic Porphyria. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537178/
- Anderson KE. Acute hepatic porphyrias: Current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-227.
Cystinosis
Overview
Nephropathic cystinosis is a rare, monogenic autosomal-recessive disease belonging to the family of lysosomal storage disorders. It is caused by mutations in the CTNS gene encoding cystinosin, a lysosomal proton/cystine cotransporter.
Defective cystinosin is unable to export cystine out of the lysosome into the cytoplasm, leading to the formation of crystals. Given that cystinosin is expressed throughout the body, cystinosis is a systemic disease in which multiple organs are affected; however, the kidneys are most vulnerable1, 2.
Extrarenal manifestations of nephropathic cystinosis include the eyes, thyroid, pancreas, gonads, muscles, bones, and central nervous system.
There are three recognized clinical phenotypes of cystinosis: infantile nephropathic cystinosis, late-onset (juvenile) nephropathic cystinosis, and ocular (adult) cystinosis.
Infantile cystinosis is the most common form with the most severe phenotype (95% of cystinosis patients). Although cystine accumulation starts in utero, patients with infantile cystinosis usually are asymptomatic at birth and have normal development during the first 3–6 months of life2, 3. However, these patients develop manifestations ofrenal Fanconi syndrome (RFS) and typically progress to end-stage kidney disease (ESKD) within the first 12 years of their life when left untreated.
By contrast, patients with juvenile cystinosis present with milder manifestations and with late onset as well as a lower rate of progression2, 4. These patients are usually diagnosed in their childhood or during adolescence, but can also present as proteinuric chronic kidney disease (CKD) and may maintain renal function until the age of 30–402,5. Renal involvement in the non-infantile patient is largely heterogenous, even within the same family.
The adult, non-nephropathic ocular form of cystinosis has no systemic involvement and is characterized only by photophobia due to cystine crystal dep5.
Cystinosis has a general incidence rate of 0.5–1 per 100 000 live births [95,96]. Higher local incidence rates of cystinosis have been reported in Brittany (Northwestern France) and Saguenay (Québec, Canada) due to the prevalence of specific CTNS mutations in these populations. Since cystinosis is a monogenic autosomal-recessive disease, patients normally have biallelic mutations in the CTNS gene (chromosome 17 p13.2), resulting in loss of functional cystinosin (also known as PQLC4). As a recessive disease, cystinosis incidence may be correlated with consanguinity2.
The treatment includes non-specific and specific goals:
- Non-specific, symptomatic treatment of the renal Fanconi syndrome includes providing appropriate nutrition and substituting renal losses; these are crucial to allow satisfactory growth. After kidney transplantation patients require immunosuppressive therapies. Additional treatments may be necessary to treat extra-renal manifestations such as hypothyroidism or diabetes.
- Specific cystine-depleting treatment with cysteamine currently represents the mainstay of therapy, allowing depletion of lysosomal cystine in most tissues. It should be initiated as early as possible and continued lifelong. Although cysteamine does not cure the disease, it dramatically improves the overall prognosis. Oral cysteamine has no effect on corneal cystine crystals [57–59]. Patients need to be treated topically with cysteamine hydrochloride eye drops that dissolve crystals and alleviate symptoms at all ages6.
Diagnosis
Diagnosis should be made as soon as possible, because early initiation of cysteamine treatment has a considerable impact on the long-term prognosis. At least 50% of children worldwide are diagnosed beyond 1 year of age, unless other affected siblings are present in the family.
Since cystinosis is the most common hereditary cause of renal Fanconi syndrome in young children, cystinosis should always be suspected in children presenting with the above listed symptoms. Urine dipstick usually shows low specific gravity, overt glucosuria and mild albuminuria. Serum creatinine is generally normal in young children, unless patients are dehydrated.
The diagnosis can be confirmed by performing the following tests:
- measurement of leukocyte cystine levels (LCL);
- demonstration of corneal cystine crystals by the slit lamp exam and
- genetic analysis of the CTNS gene6.
Symptoms and clinical presentation
Cystine accumulation begins during fetal life and affects all tissues. Cell damage and organ dysfunction, however, are heterogeneous and vary in severity and progression.
At birth, renal tubular function appears well preserved. The renal Fanconi syndrome usually manifests by 4–6 months of age with polyuria, polydipsia, failure to thrive, vomiting, constipation, dehydration, growth retardation and/or rickets, in association with biochemical evidence of proximal tubular dysfunction. This includes substantial losses of electrolytes, low-molecular weight proteinuria and severe acidosis; hypophosphatemia and impaired calcitriol metabolism often cause severe rickets. Without treatment with cysteamine, renal function declines with time, causing ESRD at ∼10–12 years of age.
Corneal cystine crystals are usually visible by a slit lamp exam after the first year of life. Cystine accumulation in thyroid follicular cells causes fibrosis, atrophy and dysfunction of the thyroid gland in 75% of patients by the age of 10 years. Males develop hypergonadotropic hypogonadism; testosterone replacement therapy allows pubertal development in males, but does not prevent infertility, which is invariably observed. Conversely, female patients usually have pubertal retardation, but their gonadal function is not as severely compromised and successful pregnancies have been reported.
Pancreatic dysfunction can cause insulin-dependent diabetes mellitus in the second and third decade of life. Lysosomal cystine accumulation also causes hepatomegaly and splenomegaly in approximately one-third of subjects by the age of 15 years.
In young adults, cystine deposition in muscles causes generalized muscle atrophy and muscle weakness, initially involving the distal extremities.
Pulmonary dysfunction parallels the severity of the myopathy and causes severe exercise intolerance and respiratory failure.
Generally, patients have normal intelligence. However, mild neurocognitive abnormalities have been reported even in very young children and could be related to abnormalities in the cerebral white matter microstructure.
Despite successful renal transplantation, many patients do not survive past the age of 30 years if they have not been treated with cysteamine6.
Causes
The three clinical forms of cystinosis are caused by bi-allelic mutations in the CTNS gene (17p13.2) that encodes the lysosomal cystine transporter cystinosin. Current evidences indicate that cystinosis is a monogenic-recessive disease with complete penetrance. Severe truncating mutations cause infantile cystinosis, while milder mutations in at least one allele are usually observed in late-onset and ocular forms. More than 100 mutations have been reported. The most frequent mutation, affecting ∼76% of northern European alleles, is a large deletion of 57 257 base pairs involving the first 9 CTNS exons and part of exon 106.References
- Cherqui S, Courtoy PJ. The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat Rev Nephrol. 2017 Feb;13(2):115-131.
- Jamalpoor A, Othman A, Levtchenko EN, Masereeuw R, Janssen MJ. Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis. Trends Mol Med. 2021 Jul;27(7):673-686.
- Wilmer, M.J., Schoeber, J.P., van den Heuvel, L.P. et al. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol 26, 205–215 (2011).
- Bäumner S, Weber LT. Nephropathic Cystinosis: Symptoms, Treatment, and Perspectives of a Systemic Disease. Front Pediatr. 2018 Mar 14;6:58.
- Servais A, Morinière V, Grünfeld JP, Noël LH, Goujon JM, Chadefaux-Vekemans B, Antignac C. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol. 2008 Jan;3(1):27-35.
- Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van’t Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014 Sep;29 Suppl 4(Suppl 4):iv87-94.
Hyperammonaemia
Overview
Hyperammonemia is a metabolic condition characterized by raised levels of ammonia, a nitrogen-containing compound. Ammonia is a potent neurotoxin. Hyperammonemia most commonly presents with neurological signs and symptoms that may be acute or chronic, depending on the underlying abnormality. Hyperammonemia should be recognized early and treated immediately to prevent the development of life-threatening complications such as cerebral edema and brain herniation1.
Typical clinical features of hyperammonemia include neurological signs and symptoms due to its neurotoxic effects.
Early-onset hyperammonemia is seen in neonates at 24-72 hours of life. The neonate becomes symptomatic as ammonia levels rise above 100-150 micromol/L. The family usually gives a history of non-specific symptoms, including lethargy, irritability, and vomiting. As the levels rise, the child may develop hyperventilation and grunting as the ammonium ion stimulates the medullary center of the brain responsible for controlling respiration.
Late onset hyperammonemia presents later in life and occurs because of multiple congenital and acquired disorders. Symptoms include irritability, headache, vomiting, ataxia, and gait abnormalities in the milder cases. Seizures, encephalopathy, coma, and even death can occur in cases with ammonia levels greater than 200 micromol/L. Patients with partial defects in urea cycle enzymes develop symptoms only during stressful periods e.g., starvation, pregnancy, surgery, etc2. Symptoms may also be precipitated due to an increase in protein intake, constipation, aggressive diuresis, use of opioids, or infections like spontaneous bacterial peritonitis.
Patients may develop intellectual disability, behavioral and psychiatric symptoms in chronic hyperammonemia. This has been linked to glutamine levels in the brain3.
Inborn errors (genetic disorders) of metabolism inducing hyperammonemia, among the others, are N-Acetylglutamate Synthetase Deficiency (NAGSD), Propionic Acidemia (PA), Methylmalonic Acidemia (MMA) and Isovaleric Acidemia (IVA), all autosomal recessive4.
NAGSD is the rarest defect of the urea cycle, with an incidence of less than one in 2,000,000 live births5.
The pooled prevalence of PA estimates indicated detection rates of 0.29; 0.33; 0.33 and 4.24 in the Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, per 100,000, newborns respectively6.
The pooled prevalence of MMA worldwide is estimated 1.14 per 100,000 newborns7.
Prevalence of IVA is estimated to be 1 in 90,000–100,000 newborns worldwide8.
Treatment goal for patients of acute hyperammonemia focuses on decreasing the level of ammonia and controlling specific complications, including cerebral edema and intracranial hypertension. Inborn errors of metabolism may lead to neonatal onset hyperammonemia or may present as intercurrent episodes of hyperammonemia1.
Neonates with inborn errors of metabolism may present with hyperammonemic coma, a serious condition requiring immediate intervention. All protein intake should be stopped, and calories should be provided using glucose solutions1.
Hemodialysis and peritoneal dialysis for the rapid removal of ammonia were frequently used in the past, while, nowadays specific pharmacological treatments allow to avoid them8.
Diagnosis
The first step of hyperammonemia diagnosis is to quantify the ammonia blood level of the patient. Normal levels are mentioned below:- Healthy term infants: 45±9 micromol/L; 80 to 90 micromol/L is the upper limit of normal.
- Preterm infants: 71±26 micromol/L, decreasing to term levels in approximately seven days
- Children older than 1 month: less than 50 micromol/L
- Adults: less than 30 micromol/L
References
- Ali R, Nagalli S. Hyperammonemia. [Updated 2023 Apr 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557504/
- Vaquero J, Chung C, Cahill ME, Blei AT. Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis. 2003 Aug;23(3):259-69.
- Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest. 2007 Oct;132(4):1368-78.
- Alfadhel M, Al Mutairi F, Makhseed N, Al Jasmi F, Al-Thihli K, Al-Jishi E, Al-Sayed M, Al-Hassnan ZN, Al Murshedi F, Häberle J, Ben-Omran T. Therapeutics and Clinical Risk Management 2016:12 479–487.
- Singh, R.H., Bourdages, MH., Kurtz, A. et al. The efficacy of Carbamylglutamate impacts the nutritional management of patients with N-Acetylglutamate synthase deficiency. Orphanet J Rare Dis 19, 168 (2024).
- Almási, T., Guey, L.T., Lukacs, C. et al. Systematic literature review and meta-analysis on the epidemiology of propionic acidemia. Orphanet J Rare Dis 14, 40 (2019).
- Jin L, Han X, He F, Zhang C. Prevalence of methylmalonic acidemia among newborns and the clinical-suspected population: a meta-analyse. J Matern Fetal Neonatal Med. 2022 Dec;35(25):8952-8967.
- Reigstad H, Woldseth B, Häberle J. Normal Neurological Development During Infancy Despite Massive Hyperammonemia in Early Treated NAGS Deficiency. JIMD Rep. 2017;37:45-47. Zaunseder E, Mütze U, Garbade SF, Haupt S, Feyh P, Hoffmann GF, Heuveline V, Kölker S. Machine Learning Methods Improve Specificity in Newborn Screening for Isovaleric Aciduria. Metabolites. 2023 Feb 18;13(2):304.
